This invention relates to compounds, pharmaceutical compositions, and methods for the treatment or prevention of seizures, epilepsy, tremors, affective disorders, obesity, neuropathic pain, and migraines.
2.1. Topiramate
Topiramate is a sulfamate-substituted monosaccharide, which is chemically named 2,3:4,5-Di-O-isopropylidene-xcex2-D-fructopyranose sulfamate. The molecular formula of topiramate is C12H21NO8S, and its chemical structure is represented by formula I: 
Topiramate is a white crystalline powder with a solubility in water of 9.8 mg/mL, and it is freely soluble in acetone, chloroform, dimethylsulfoxide, and ethanol. See, Physician""s Desk Reference, 56th ed., pp. 2590-2595 (2002).
Topiramate is sold in the United States under the trade name TOPAMAX(copyright) (Ortho-McNeil Pharmaceutical, Inc., Raritan, N.J., U.S.A.). TOPAMAX(copyright) has been approved for use as an antiepileptic agent as an adjuvant therapy for patients with partial onset seizures, or primary generalized tonic-clonic seizures. See generally, Physician""s Desk Reference, 56th ed., 2590-2595 (2002); see also, U.S. Pat. No. 4,513,006. Adverse effects associated with the administration of topiramate include, but are not limited to, somnolence, dizziness, ataxia, speech disorders and related speech problems, psychomotor slowing, abnormal vision, difficulty with memory, paresthesia, diplopia, renal calculi (kidney stones), hepatic failure, pancreatitis, renal tubular acidosis, acute myopia and secondary angle closure glaucoma. Physician""s Desk Reference, 56th ed., pp. 2590-2595 (2002).
Topiramate has been investigated for use as anti-obesity agent, a blood pressure lowering agent, and a mood stabilizer, including use as an antimanic, antidepressant, and for the treatment of post-traumatic stress disorder, migraines, cluster headaches, and neuropathic pain. See, e.g., U.S. Pat Nos. 6,191,117; 6,201,010; 5,753,693; 5,998,380; 6,319,903; 5,935,933; and 5,760,007. However, the time it takes for topiramate to reach peak plasma levels (i.e., about two hours) may be too slow for its effective use in the treatment of some conditions, such as neuropathic pain. Moreover, the compound""s relatively low aqueous solubility makes it difficult to provide in a controlled release dosage form, which may be necessary for the effective treatment of conditions such as obesity, and which may allow a reduction in adverse effects associated with peak plasma levels of the drug. Therefore, new highly soluble and bioavailable forms of topiramate are needed in order to increase the safety and effectiveness of the compound.
2.2. Epilepsy, Seizures, and Tremors
Epilepsy is a chronic disorder or condition characterized by recurring motor, sensory, or behavioral or psychic alterations or malfunctions that can include unconsciousness or convulsive movements. See Valente L R, Clinician Reviews, 10(3): 79 (2000). A variety of seizure types can occur, from partial seizures to generalized seizures.
There are three classifications of partial seizures: simple, complex, and secondarily generalized. A patient with a simple partial seizure (also called Jacksonian seizure) may experience jerking or shaking in one area of the body, which may progress to other areas. A simple partial seizure may also manifest with somatosensory, visual, auditory, olfactory, autonomic (sweating, pupillary dilation, epigastric rising), or psychic symptoms. With complex partial seizures, the patient""s consciousness may be impaired, either immediately, or gradually over time after simple partial onset. Patients experiencing a complex partial seizure will often exhibit a blank stare followed by automatism, which may include lip smacking, chewing, picking at clothing, or purposeless walking. Finally, secondarily generalized seizures can evolve directly from simple partial or complex partial seizures, or progress from simple partial to complex partial to generalized. See, Leppik I E. Contemporary Diagnosis and Management of the Patient With Epilepsy. 4th Ed., Newtown, Pa.: Handbooks in Health Care Co (1999).
Generalized seizures can be convulsive or nonconvulsive, but always involve a loss of consciousness. Absence seizures (formerly called xe2x80x9cpetit malxe2x80x9d) may be typical or atypical, and are strongly linked to genetic predisposition. Typical absence seizures may be precipitated by photic stimulation or hyperventilation. The symptoms include a blank stare, eye blinking, and in some instances automatisms, and the patient may experience increased or decreased tone. These brief seizures tend to occur in groups, and can occur 50 to 100 times in a day. See, Leppik I E. Contemporary Diagnosis and Management of the Patient With Epilepsy. 4th Ed., Newtown, Pa.: Handbooks in Health Care Co (1999). Atypical absence seizures, begin and end less abruptly the typical absence seizures, but last longer and result in more pronounced changes in tone.
Myoclonic seizures manifest with quick, involuntary muscle jerks lasting a few seconds. These muscle jerks or movements may be isolated to one body part or involve the entire body. Myoclonic seizures may accompany other generalized seizures and are common to specific epilepsy syndromes. Tonic seizures are generally associated with other epileptic syndromes, and typically last less than a minute. Tonic seizures involve violent spasm or stiffening, and in many instances, the lower extremities are extended and the upper extremities are flexed. In addition, the patient may turn the head or eyes to one side. Clonic seizures, most common in neonates and children, also exhibit repetitive muscular jerks but at a slower rate, and while clonic seizures can last as long as several minutes, brief episodes are more common. See, Leppik I E. Contemporary Diagnosis and Management of the Patient With Epilepsy. 4th Ed., Newtown, Pa.: Handbooks in Health Care Co (1999).
Generalized tonic-clonic seizures (also called xe2x80x9cgrand malxe2x80x9d) are the ones most commonly identified with epilepsy and are the most dramatic. They can occur at any age but are rare in very young infants. See Morton et al., xe2x80x9cDiagnosis and treatment of epilepsy in children and adolescentsxe2x80x9d, Drugs. 51:399-414 (1996). They start with a sudden-onset tonic phase, typically lasting less than a minute, and all of the skeletal muscles contract at once, causing the patient to fall stiffly. In addition, the patient""s diaphragm and chest muscles will contract, forcing out air in an sigh or xe2x80x9cepileptic cry.xe2x80x9d During the clonic phase, the patient may clench the jaws, biting the inside of the cheek or side of the tongue with the molars, and consciousness may not return for 10 to 15 minutes. The patient will often be left feeling confusion, fatigue, and headache, which can last several hours to several days. See, Leppik I E. Contemporary Diagnosis and Management of the Patient With Epilepsy. 4th Ed., Newtown, Pa.: Handbooks in Health Care Co (1999).
Atonic seizures result in a sudden loss of postural tone, causing the patient to fall. In a few seconds, the patient will regain full consciousness. Atonic seizures are commonly associated with other seizure types and are common in Lennox-Gastaut syndrome. See, Leppik I E. Contemporary Diagnosis and Management of the Patient With Epilepsy. 4th Ed., Newtown, Pa.: Handbooks in Health Care Co (1999).
Other epileptic conditions include juvenile myoclonic epilepsy and Lennox-Gastaut syndrome. Juvenile myoclonic epilepsy often begins during the teenage years, and is a generalized, idiopathic epileptic syndrome, often exhibiting three seizure types: myoclonic, absence, and generalized tonic-clonic. Many patients will manifest clumsiness or jitters, which are exacerbated by stress. Lennox-Gastaut syndrome may be symptomatic (brain lesion identified) or cryptogenic (brain lesion assumed), and the generalized syndrome may include atypical absence, tonic, atonic, and tonic-clonic seizures. Often, patients suffering from Lennox-Gastaut syndrome will have varying degrees of psychomotor retardation. See, Leppik I E. Contemporary Diagnosis and Management of the Patient With Epilepsy. 4th Ed., Newtown, Pa.: Handbooks in Health Care Co (1999); and Beaumanoir et al., xe2x80x9cThe Lennox-Gastaut syndromexe2x80x9d, In: Roger et al., xe2x80x9cEpileptic Syndromes in Infancy, Childhood, and Adolescencexe2x80x9d, 2nd Ed., London, England: John Libby, pp. 231-244 (1992).
Currently, there are a number of drugs available that are used to treat epilepsy or epileptic conditions, and they are commonly referred to as anticonvulsants or antiepileptics. These drugs include older anticonvulsants, such as phenobarbital, primidone, and phenytoin, and more recent anticonvulsants, such as carbamazepine; valproic acid; felbamate; gabapentin; lamotrigine; tiagabine; topiramate; levetiracetam, and oxacarbazepine. In most cases, the newer anticonvulsants are approved as adjunctive therapy for use in conjunction with other anticonvulsants, although some of these have been approved or demonstrated efficacy as a monotherapy. See U.S. Pat. No. 6,309,406.
Common tremors, including essential, familial, and senile tremors, are relatively common in people over forty, but can also result from or be made worse by stimulants (e.g., caffeine) or during periods of stress or anxiety. In the beginning, tremors may be localized in the upper extremities, such as the hands, but can also include movements or nodding of the head, with both often occurring as a patient ages. In addition, the lips, tongue, jaw, and larynx may be involved in tremors, and they can sometimes result in a noticeable quiver in the voice of the patient.
The most common treatment for tremors are beta-blockers (e.g., propanolol) and sedatives (such as benzodiazepines and barbituates). In addition, some patients may xe2x80x9cself-medicatexe2x80x9d using alcohol due to its sedative properties.
2.3. Obesity
Obesity is one of the most prevalent medical disorders afflicting humans today, affecting more than 30% of the population. Obesity can result in a number of other medical conditions or complications, including hypertension, cardiovascular disease, diabetes mellitus, insulin resistance, sleep apnea, cholecystitis, osteoarthritis, and cancer. Body mass index, or BMI, is common used to measure obesity, and is calculated by dividing the patient""s weight in kilograms divided by their height in meters squared. The severity or degree of obesity is then determined by comparing a patient""s BMI with standard deviations above the BMI means for males and females.
At present, scientists do not know the exact etiology of obesity, although generally it occurs when energy intake exceeds energy expenditure. In addition, it appears that genetic predisposition may play a role in the amount and distribution of body fat in a patient, and this may also be under some hormonal control.
2.4. Neuropathic Pain
Neuropathic pain describes pain that is associated with damage or permanent alteration of the peripheral or central nervous system. Neuropathic pain includes, but is not limited to, neuralgia, trigeminal neurologia, diabetic neuropathy and other forms of nerve damage, allodynia, paraesthesia, hyperaesthesia, phantom pain, phantom limb pain, hyperalgesia, and tinnitus. See Taylor and Meldrum, Trends Pharmacol. Sci., 16:309-316 (1995); and Simpson and Davies, Trends Pharmacol. Sci., 20:12-18 (1999). Clinical manifestations of neuropathic pain include a sensation of burning or electric shock, feelings of bodily distortion, allodynia and hyperalgesia. The term allodynia describes the phenomenon of the perception of stimuli which are not painful per se, such as contact or heat/cold, as pain. See Rogers and Valley, Clin Podiatr Med Surg., 11(1): 73-83 (January 1994). 2.5. Other Disorders
Manic-depressive illnesses, such as manic-depressive bipolar disorder, are progressive psychiatric disorders of unknown etiology, although there are some hypotheses that recurrences of manic-depressive illness arise by electrophysiologic kindling. See, Goodwin and Jamison, Manic-Depressive Illness, Oxford University Press, New York, pp. 405-407 (1990). It is believed that topiramate may be useful in treating manic-depressive illnesses, as it has been shown to be effective in blocking kindled seizures in rats. See U.S. Pat. No. 5,753,693; and Wauquier et al., Epilepsy Res., 24:73-77 (1996).
Migraine is a neurological disorder that is characterized by recurrent attacks of headache, with pain most often occurring on one side of the head, accompanied by various combinations of symptoms such as nausea, vomiting, and sensitivity to light and sound. The migraine can occur at any time of day or night, but occurs most frequently on arising in the morning. Routine activity or slight head movement typically makes the pain worse. These episodes can last from several hours to several days and are often disabling. During the attack the pain may migrate from one part of the head to another, and may radiate down the neck into the shoulder. Scalp tenderness occurs in the majority of patients during or after an attack.
Migraine with aura, or classic migraine, refers to a severe, throbbing headache that is often preceded by visual, motor, or sensory symptoms, called an xe2x80x9caura.xe2x80x9d Migraines can also occur without an aura, which is called common migraine.
Migraine is familial and often hereditary, and is most common in women, particularly young adult women. Common characteristics of migraine include: moderate to severe headache lasting from four to 72 hours; pain that is often, but not always, located on one side of the head and throbbing; pain is aggravated by moving or physical activity; pain is often accompanied with nausea, vomiting, sensitivity to light, sound, and odors. Following a migraine attack, many patients will feel tired, washed out, irritable, or listless or have impaired concentration.
There are a number of drugs that are currently available for prophylactic treatment of migraine, including propanolol, amitriptyline, valproate, phenelzine, and methysergid, as well as aspirin-like drugs, including aspirin, naproxen, ibuprofen, mefenamic acid, flufenamic acid, and tolfenamic acid. Typically, these drugs must be taken daily, and some are associated with severe adverse effects or the high dosage amounts required for effectiveness make them undesirable. In any event, the estimated probability of success with any one of these prophylactic antimigraine drugs is about 60 to 75%. See, Harrison""s Principles of Internal Medicine, eds. Isselbacher et al., McGraw-Hill, Inc., New York, p. 69 (1994).
Cluster headache (also called xe2x80x9cmigrainous neuralgiaxe2x80x9d) has been recognized for over 100 years, although the condition has been given many different names, such as erythroprosopalgia, Raeder""s syndrome, spenopalatine neuralgia, ciliary neuralgia, vidian neuralgia, and histamine cephalalgia. There are several types of cluster headaches, including: the episodic type, which is the most common, is characterized by one to three short-lived attacks of periorbital pain per day over a 4 to 8 week period, followed by a pain-free interval; the chronic form, also called chronic migrainous neuralgia, which may begin without previous occurrence of episodic type cluster headache, or several years after an episodic pattern, and is characterized by the absence of sustained periods of remission. See A. Kudrow, xe2x80x9cThe pathogenesis of a cluster headachexe2x80x9d, Curr. Opin. Neurol., 7:278-282 (1994).
The pain associated with a cluster headache starts quickly, without warning, and is often excruciating in intensity, and is deep, nonfluctuating, and explosive in quality; only occasionally is it pulsatile. Pain usually begins in, around, or above the eye or the temple, although occasionally the face, neck, ear, or hemicranium may be affected. It is always unilateral, and generally affects the same side in subsequent bouts. Periodicity is a characteristic feature in most cluster headache patients, with attacks lasting from ten minutes to several hours, often repeating in very close intervals, and many also experience additional attacks that occur randomly throughout the day.
The most common associated symptom of cluster headache is lacrimation from the eye on the affected side. In addition, a blocked nasal passage, rhinorrhea, red eye, and sweating and pallor of the forehead and cheek are often found, but their absence does not exclude the diagnosis. A transitory, partial Homer""s syndrome (pupillary miosis and lid ptosis) occurs in two-thirds of patients when they are examined during attacks, and is highly characteristic of the cluster headache syndrome and, after repeated occurrences, may become a permanent feature.
Cluster headache more often afflicts men than women, and most patients begin experiencing headache between the ages of 20 and 50 years, though cluster headaches can start to occur as early as the first decade and as late as the eighth decade.
This invention encompasses salts of topiramate, and polymorphs, solvates, hydrates, dehydrates, co-crystals, anhydrous, and amorphous forms thereof. The invention further encompasses pharmaceutical compositions and dosage forms comprising pharmaceutically acceptable salts of topiramate, and polymorphs, solvates, hydrates, dehydrates, co-crystals, anhydrous, and amorphous forms thereof. Specific salts encompassed by the invention include, but are not limited to, topiramate sodium, topiramate lithium, and topiramate potassium. Specific co-crystals encompassed by the invention include, but are not limited to, co-crystals or complexes of caffeine. Certain pharmaceutical compositions and dosage forms of the invention also comprise at least one additional anticonvulsant or antiepileptic agent.
The invention further provides methods of treating and preventing conditions in a patient that include, but are not limited to, seizures, convulsions, epileptic conditions, tremors, cerebral function disorders, obesity, neuropathic pain, affective disorders, migraines, and cluster headaches. Methods of the invention comprise administering to a patient in need of such treatment or prevention a therapeutically or prophylactically effective amount of a pharmaceutically acceptable salt of topiramate, or a polymorph, solvate, hydrate, dehydrate, co-crystal, anhydrous, and amorphous form thereof. In a preferred embodiment, the topiramate salt is topiramate sodium, topiramate lithium, topiramate potassium, or a polymorph, solvate, hydrate, dehydrate, co-crystal, anhydrous, or amorphous form thereof. Specific co-crystals of topiramate salts are co-crystals or complexes of caffeine.
Additional methods of the invention comprise adjunctively administering to a patient a therapeutically or prophylactically effective amount of a pharmaceutically acceptable salt of topiramate, or a polymorph, solvate, hydrate, dehydrate, co-crystal, anhydrous, and amorphous form thereof, and at least one additional anticonvulsant or antiepileptic agent.
3.1. Definitions
As used herein and unless otherwise indicated, the term xe2x80x9cpatientxe2x80x9d includes mammals, and preferably humans.
As used herein and unless otherwise indicated, the term xe2x80x9ctopiramatexe2x80x9d refers to 2,3:4,5-Di-O-isopropylidene-xcex2-D-fructopyranose sulfamate and isomers and mixtures of isomers thereof. In particular, while xe2x80x9ctopiramatexe2x80x9d conventionally refers to the specific compound named 2,3:4,5-Di-O-isopropylidene-xcex2-D-fructopyranose sulfamate and represented by formula I, above, the term is used herein to refer to all enantiomerically and/or diastereomerically pure isomers of that specific compound, as well as mixtures of such isomers. In other words, the term xe2x80x9ctopiramate,xe2x80x9d as used herein unless otherwise indicated, encompasses sulfamic acid 2,2,7,7-tetramethyl-tetrahydro-bis[1,3]dioxolo[4,5-b;4xe2x80x2,5xe2x80x2-d]pyran-3a-ylmethyl ester, which is represented by formula II: 
and enantiomerically and diastereomerically pure forms thereof, as well as mixtures of such forms. Specific mixtures comprise about 10, 20, 30, 40, or 50 weight percent one enantiomer or diastereomer and about 90, 80, 70, 60, or 50 weight percent of another enantiomer or diastereomer of the compound.
As used herein and unless otherwise indicated, the term xe2x80x9csaltxe2x80x9d encompasses salts that are pharmaceutically acceptable, as well as those that are not. Salts that are not pharmaceutically acceptable are preferably not administered to patients, but may be used to provide, for example, intermediate or bulk forms of drugs.
As used herein and unless otherwise indicated, the terms xe2x80x9cpharmaceutically acceptable saltxe2x80x9d or xe2x80x9cpharmaceutically acceptable base addition saltxe2x80x9d refers to a salt prepared with various pharmaceutically acceptable bases. Bases that can be used to prepare pharmaceutically acceptable salts are those that form non-toxic base addition salts, i.e., salts containing pharmacologically acceptable cations, such as, but not limited to, sodium, potassium, lithium, magnesium, calcium, aluminum, zinc, procaine, benzathine, chloroprocaine, choline, diethylamine, ethylenediamine, N-methylglucamine, benethamine, clemizole, dietheylamine, piperazine, tromethamine, triethylamine, ethanolamine, triethanolamine, arginine, lysine, histidine, tributylamine, 2-amino-2-pentylpropanol, 2-amino-2-methyl-1,3-propanediol, tris(hydroxymethyl)aminomethane, benzylamine, 2-(dimethylamino)ethanol, barium or bismuth counter ions. Particularly preferred cations are sodium, lithium, and potassium. The most preferred cation is sodium.
As used herein and unless otherwise indicated, the term xe2x80x9cadjunctively administeringxe2x80x9d refers to the administration of one or more compounds or active ingredients in addition to a pharmaceutically acceptable salt of topiramate, or polymorph, solvate, hydrate, dehydrate, co-crystal, anhydrous, or amorphous form thereof, either simultaneously with the same or at intervals prior to, during, or following administration of the pharmaceutically acceptable salt of topiramate to achieve the desired therapeutic or prophylactic effect.
As used herein, the term xe2x80x9cseizuresxe2x80x9d includes but is not limited to, partial seizures, including without limitation: simple partial seizures, complex partial seizures, and secondarily generalized seizures; generalized seizures, including without limitation absence seizures (also called xe2x80x9cpetit malxe2x80x9d) typical absence seizures, atypical absence seizures, myoclonic seizures, tonic seizures, clonic seizures, generalized tonic-clonic seizures (also called xe2x80x9cgrand malxe2x80x9d), and atonic seizures; and seizures associated with juvenile myoclonic epilepsy and Lennox-Gastaut syndrome.
As used herein and unless otherwise indicated, the term xe2x80x9cepileptic conditionxe2x80x9d refers to epilepsy, juvenile myoclonic epilepsy, and Lennox-Gastaut syndrome.
As used herein and unless otherwise indicated, the term xe2x80x9ccerebral function disorderxe2x80x9d includes, but is not limited to, disorders involving intellectual deficits such as senile dementia, Alzheimer""s type dementia, memory loss, amnesia/amnesic syndrome, disturbances of consciousness, coma, lowering of attention, speech disorders, Parkinson""s disease, autistic disorder, autism, hyperkinetic syndrome, and schizophrenia. Also within the meaning of the term are disorders caused by cerebrovascular diseases (including, but not limited to, cerebral infarction, cerebral bleeding, cerebral arteriosclerosis, cerebral venous thrombosis, head injuries, and the like) where symptoms include disturbance of consciousness, senile dementia, coma, lowering of attention, and speech disorders.
As used herein and unless otherwise indicated, the term xe2x80x9cmethod of treating Parkinson""s diseasexe2x80x9d means relief from the symptoms of Parkinson""s disease, which include, but are not limited to, a slowly increasing disability in purposeful movement, tremors, bradykinesia, ticks, rigidity, and posture disturbance.
As used herein and unless otherwise indicated, the term xe2x80x9ctremorsxe2x80x9d refers to familial, essential and senile tremors.
As used herein and unless otherwise indicated, the term xe2x80x9ca method for treating obesity or weight gainxe2x80x9d means reduction of weight, relief from being overweight, relief from gaining weight, or relief from obesity, all of which are usually due to extensive consumption of food.
As used herein and unless otherwise indicated, the term xe2x80x9cneuropathic painxe2x80x9d includes, but is not limited to, neuralgia, trigeminal neurologia, diabetic neuropathy and other forms of nerve damage, allodynia, paraesthesia, hyperaesthesia, phantom pain, phantom limb pain, hyperalgesia, and tinnitus.
As used herein and unless otherwise indicated, the term xe2x80x9caffective disorderxe2x80x9d includes, but is not limited to, manic conditions (e.g., acute mania), manic rapid cycling, bipolar mood disorders or conditions (e.g., manic-depressive bipolar disorder), mood stabilization, post-traumatic stress disorder, depression, anxiety disorders, attention deficit disorder, attention deficit disorder with hyperactivity, compulsive or obsessive-compulsive disorder, narcolepsy, premenstrual syndrome, chronic fatigue syndrome, seasonal affective disorder, substance abuse or addiction, nicotine addiction or craving, and obesity or weight gain.
As used herein and unless otherwise indicated, the terms xe2x80x9cattention deficit disorderxe2x80x9d (ADD), xe2x80x9cattention deficit disorder with hyperactivityxe2x80x9d (ADDH), and xe2x80x9cattention deficit/hyperactivity disorderxe2x80x9d (AD/HD), are used in accordance with their accepted meanings in the art. See, e.g., Diagnostic and Statistical Manual of Mental Disorders, Fourth Ed., American Psychiatric Association, 1997 (DSM-IV(trademark)); and Diagnostic and Statistical Manual of Mental Disorders, 3rd Ed., American Psychiatric Association (1981) (DSM-III(trademark)).
As used herein and unless otherwise indicated, the term xe2x80x9cdepressionxe2x80x9d includes a disease or condition characterized by changes in mood, feelings of intense sadness, despair, mental slowing, loss of concentration, pessimistic worry, agitation, and self-deprecation. Physical symptoms of depression that may be reduced or alleviated by the methods of the invention include, but are not limited to, insomnia, anorexia, weight loss, decreased energy and libido, and abnormal hormonal circadian rhythms.
As used herein and unless otherwise indicated, the term xe2x80x9ccluster headachexe2x80x9d includes, but is not limited to, migrainous neuralgia, chronic migrainous neuralgia, erythroprosopalgia, Raeder""s syndrome, spenopalatine neuralgia, ciliary neuralgia, vidian neuralgia, histamine cephalalgia, episodic cluster headache, and chronic cluster headache.